Phosphodiesterase type 5 (PDE5) is an important enzyme involved in regulating intracellular cyclic guanosine monophosphate (cGMP) signaling. PDE5 catalyzes the hydrolysis of cGMP into 5′ guanosine monophosphate, whereby inhibition leads to increased magnitude or duration of the cGMP signal. PDE5 is an essential regulator of normal physiological processes, such as smooth muscle contraction and relaxation and may also play an important role in a variety of pathological conditions including pulmonary hypertension, cognitive function, cystic fibrosis, and cancer. For example, PDE5 is a major cGMP degrading PDE isozyme in penile corpus cavernosum tissue, whereby its inhibition by drugs such as sildenafil, vardenafil, or tadalafil can enhance penile erection upon sexual arousal.1, 2 Inhibition of PDE5 may also benefit patients with pulmonary hypertension or cystic fibrosis, while additional indications are being studied including the enhancement of cognitive function, increasing efficacy of conventional chemotherapy, as well as being cardioprotective.
Recent studies have shown that PDE5 and possibly additional cGMP-PDEs are expressed in various carcinomas such as those derived from the colon, breast, lung and bladder. Moreover, cGMP PDE inhibition and consequent high intracellular levels of cGMP may be associated with the apoptotic activities of certain drugs.4, 5 For example, exisulind and its analogs (CP78, CP461, CP248) have been reported to selectively induce apoptosis of tumor cells derived from a variety of cancers including colon, bladder, prostate, breast and lung. Exisulind and its analogs maintained similar rank order of potency to induce apoptosis and inhibit tumor cell growth compared with cGMP PDE inhibition. Such compounds also caused a sustained elevation of intracellular cGMP levels in colon tumor cells. Therefore, it is proposed that cGMP mediates the mechanism underlying the apoptosis inducing properties of exisulind in neoplastic cells.4-7 These effects in neoplastic cells appear to be not solely dependent on the specific inhibition of PDE5, but rather, are related to inhibition of additional cGMP-PDEs. Previous studies therefore indicate that it is important to inhibit multiple cGMP PDE isoforms, although the exact isozymes involved have not been well defined.7 Accordingly, highly selective and potent PDE5 inhibitors such as tadalafil would not be expected to have anticancer properties. Additionally, there may be other reasons why conventional PDE5 inhibitors do not have anticancer activity that have not yet been delineated.
Even though significant advances have occurred in the treatment of cancer, it still remains a major worldwide health concern. Notwithstanding the advances in treatments for cancer and other hyperproliferative diseases there still remains room for improved drugs that are effective with minimal toxicity.